Acquired immunodeficiency syndrome (AIDS) is caused by a retrovirus identified as the human immunodeficiency virus (HIV). The immune response to HIV infection in long-term non-progressors suggests that specific viral immunity may limit infection and the symptoms of disease. Rare HIV infected individuals show broadly neutralizing IgG antibodies in their serum but little is known regarding the specificity and activity of these antibodies despite their potential importance in designing effective vaccines. No single characteristic yet correlates with protective immunity. In animal models, passive transfer of neutralizing antibodies can also contribute to protection against virus challenge. Neutralizing antibody responses can also be developed in HIV-infected individuals and are associated with lower viral loads in long-term non-progressors. Though this neutralizing antibody response is uncommon, it is directed largely against the Env protein of the virus.
A number of immunologic abnormalities have been described in AIDS including abnormalities in B-cell function, abnormal antibody response, defective monocyte cell function, impaired cytokine production, depressed natural killer and cytotoxic cell function, and defective ability of lymphocytes to recognize and respond to soluble antigens. Other immunologic abnormalities associated with AIDS have been reported. Among the more important immunologic defects in patients with AIDS is the depletion of the T4 helper/inducer lymphocyte population.
The HIV env protein has been extensively described, and the amino acid and RNA sequences encoding HIV env from a number of HIV strains are known (Modrow, S. et al., J. Virology 61(2): 570 (1987). The HIV virion is covered by a membrane or envelope derived from the outer membrane of host cells. The membrane contains a population of envelope glycoproteins (gp 160) anchored in the membrane bilayer at their carboxyl terminal region. Each glycoprotein contains two segments. The N-terminal segment, called gp120 by virtue of its relative molecular weight of about 120 kD, protrudes into the aqueous environment surrounding the virion. The C-terminal segment, called gp41, spans the membrane. gp120 and gp 41 are covalently linked by a peptide bond that is particularly susceptible to proteolytic cleavage. McCune et al., EPO Application No. 0 335 635, priority 28 Mar. 88 and references cited therein, herein incorporated by reference.
Several approaches to an AIDS vaccine have been proposed, including inactivated and attenuated virus vaccines, subunit vaccines from virus-infected cells, recombinantly produced viral antigens, vaccines based on synthetic peptides, anti-idiotypic vaccines, and viral carrier-based vaccines, however no vaccination study published to date has provided protection against challenge with virus. Several reviews of HIV vaccine development have been published, e.g. Lasky, (1989), Newmark, (Jun. 23, 1988), and Fauci et al., (1 Mar. 1989).
However, there have been problems including reversion of attenuated virus vaccines; soliciting partial immune response; not eliciting cellular immunity; and the variability and mutability of HIV itself. These problems have frustrated the development of HIV therapies.
Other approaches to HIV therapeutic and prophylactic treatments have included making highly neutralized antibodies for HIV treatment. There have been many years of extensive HIV research in cloning and making monoclonal antibodies by various techniques for targeting CD4 and for neutralizing HIV. These techniques usually involve self-fusion or phage display techniques. A limited number of monoclonal antibodies produced so far are broadly neutralizing to HIV. Among those broadly neutralizing monoclonal antibodies is the phage display antibody, B12. Typically, in making HIV neutralizing antibodies using phage display techniques, random combinations of heavy and light chains are combined and a random pair is selected; in this instance, B12 was shown effective. Monoclonal antibody B12 is a broadly neutralizing antibody which prevents HIV infection in Macaques. Another broadly neutralizing antibody includes 2G12, which, atypically, has a structure which has yet to be seen in any other antibody with three combining sites. The structure of 2G12 has yet to be reproduced.
It has been found that certain people develop antibodies to HIV, which are broadly neutralizing antibodies, which means that their antibodies can neutralize many strains of HIV in their sera. While such patients do not cure their own infection, they are able to inhibit it. When the antibody sees the virus, the virus mutates away from the antibody. These people continue to make antibodies even as the virus keeps mutating. Antibodies can be protective against initial HIV infection in passive transfer experiments in non-human primates and can modulate viral load during infection. Mascola, 2000; Shibata, 1999; Veazey, 2003; Parren, 2001; Mascola, 1999; Trkola, 2005; Wei, 2003; Frost, 2005. Based on these observations, it has been proposed that such antibodies may be important components of a preventative vaccine. Burton, 2004; Mascola, 2007; Karlsson Hedestam, 2008; McMichael, 2006; Zolla-Pazner, 2004.
These Rare HIV infected patients develop high titers of broadly neutralizing antibodies. But, despite intensive study over two decades, only a small number of well-characterized monoclonal antibodies broadly neutralize HIV efficiently in vitro and only a fraction of these prevent infection of non-human primates, as discussed herein, Mascola, 2000; Shibata, 1999, Veazey, 2003; Parren, 2001; Mascola, 1999. At present, broadly neutralizing antibodies from non-progressor patients and/or slow progressor patients have not been made or isolated. It is therefore a continuing need to identify and produce neutralizing antibodies for the development of HIV therapeutics and vaccines.
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